Prescribed opioid analgesic (POA) use for the treatment of pain is common among women of childbearing age and pregnant women. Despite its prevalence, however, little is known about the effects of POA use in pregnancy on offspring development. Animal models demonstrate that prenatal opioid exposure can alter brain development and behavior, but whether this translates to risks for neurodevelopmental disorders in humans is not known. Findings from the few observational studies of POA use in pregnancy and birth outcomes are mixed and limited by poor study quality, including inadequate control for confounding. The current proposal seeks to address these limitations through comprehensive analysis of a large population-based sample. In particular, the objective of the current proposal is to improve our understanding of the use and safety of POAs in pregnancy, focusing on adverse birth outcomes (structural birth defects, small size for gestational age, and preterm birth) and neurodevelopmental disorders (autism spectrum and attention-deficit/hyperactivity disorders). We propose to analyze an unparalleled, nation-wide dataset of 1.25 million Swedish children born 2006-2017, which includes detailed assessment of POA use in pregnancy, birth outcomes and neurodevelopmental disorders, and a wide range of factors that could influence the likelihood of both treatment and offspring outcomes. Furthermore we propose to use and combine multiple advanced methods of analysis. In addition to adjustment for measured factors, we will use several types of comparison groups to help evaluate the role of unmeasured confounding, including siblings, offspring of mothers using another pain medication (i.e., prescribed acetaminophen as an active comparator), and offspring of mothers using POAs before but not during pregnancy. Finally, we also will evaluate the associations with paternal POA use during pregnancy as a negative control. Preliminary analyses demonstrating that POA use during pregnancy is associated with adverse offspring outcomes, but also with many psychiatric and socioeconomic factors associated with the offspring outcomes, highlight the importance of our proposal. The proposed research is significant because it will provide a greater description of the patient characteristics that influence POA use during pregnancy, as well as a better understanding of the specific risks of the practice for offspring outcomes associated with significant morbidity and mortality. The proposal is innovative due to (a) the use of unparalleled data drawn from the linkage of numerous national registers that provide precise measures for key constructs; (b) the use of multiple advanced methods and systematic evaluation of the validity of their assumptions; and (c) a unique interdisciplinary team of researchers. The results will provide critical information for medical decision-making regarding the pain management with POAs in pregnancy and among women of childbearing age, inform ensuing research to identify offspring at greatest risk of adverse outcomes related to POA use, and guide subsequent basic research into mechanisms behind the effects of fetal opioid exposure.